This application seeks to understand the mechanisms that govern stem cell self-renewal and differentiation. Recent studies indicate that signaling through the thrombopoietin receptor, mpl, stimulates expansion of multi- lineage, long-term repopulating stem cells. Studies described in this proposal will identify and characterize the features of mpl signaling that are permissive for stem cell expansion. Experiments will be performed to determine whether mpl's ability to stimulate cell expansion is shared by the GCSF receptor. Finally, transgenic mice will be used to quantitate the magnitude and kinetics of stem cell expansion occurring in response to mpl and GCSF receptor signaling. Finally, studies will be performed to determine whether transient activation of the mpl and GCSF receptor in stem cells can influence their developmental fate.